Although strong progress has been made in the treatment of breast cancer the subclass of triple

negative breast cancer (TNBC) is till today very difficult to treat. In particular, the mesenchymal like

TNBC subtype shows increased malignant behaviour and therapy resistance. We recently identified

that the transcription factor ZEB1 is essential for the aetiology of mesenchymal-like basal breast

cancer. ZEB1 is a potent EMT (epithelial to mesenchymal transition) inducing transcription factor for

which the expression and downstream transcriptional effects are strongly correlated with poor patient

outcome. In addition, ZEB1 induction was strongly correlated with the downregulation of the Estrogen

Receptor (ER1) suggesting that EMT may be a driver of resistance to anti-estrogen therapies. Our

overall aim is to target in particular this subset of mesenchymal-like triple negative breast cancers as

there is an unmet medical need for novel therapies that will allow a better patient outcome. Therefore,

we screened a ZEB1 driven human breast cancer EMT model using an innovative EMT sensor

approach with a drug repurposing library to identify novel anti-EMT drugs. In this project we aim to

further validate and evaluate the therapeutic potential to treat TNBC with these identified anti-EMT

repurposing drugs, as we hypothesize that re-differentiation would sensitize these breast cancers for

other combination therapies. We will test the efficacy of these novel therapeutic strategy on wellestablished

mouse models of metastatic breast cancer and on human patient-derived breast cancer

xenografts (PDX) representative for this subtype of malignant breast cancer. We are convinced that

successful completion of this research project could result in rapid initiation of a planned clinical trial

with these anti-EMT repositioned drugs.